16-58001290-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000698445.1(USB1):c.-194C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 679,862 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 33)
  • Exomes 𝑓: 0.012 (58 hom.)
• Consequence: USB1 ENST00000698445.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.815

Genes affected

USB1 (HGNC:25792): (U6 snRNA biogenesis phosphodiesterase 1) This gene encodes a protein with several conserved domains, however, its exact function is not known. Mutations in this gene are associated with poikiloderma with neutropenia (PN), which shows phenotypic overlap with Rothmund-Thomson syndrome (RTS) caused by mutations in the RECQL4 gene. It is believed that this gene product interacts with RECQL4 protein via SMAD4 proteins, explaining the partial clinical overlap between PN and RTS. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-58001290-C-G is Benign according to our data. Variant chr16-58001290-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1800912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0105 (1602/152272) while in subpopulation AMR AF= 0.022 (336/15298). AF 95% confidence interval is 0.02. There are 15 homozygotes in gnomad4. There are 831 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USB1	NM_001330568.2	c.-55-1189C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USB1	ENST00000698445.1	c.-194C>G		5_prime_UTR_variant	1/6
USB1	ENST00000561743.5	c.-55-1189C>G		intron_variant		3		P1
USB1	ENST00000698444.1	c.-55-1189C>G		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1596 AN: 152154 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.0120 AC: 6330 AN: 527590 Hom.: 58 AF XY: 0.0121 AC XY: 3388 AN XY: 279382

Gnomad4 AFR exome AF: 0.00204

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.000317

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.0223

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0105 AC: 1602 AN: 152272 Hom.: 15 Cov.: 33 AF XY: 0.0112 AC XY: 831 AN XY: 74448

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00958 Hom.: 1

Bravo AF: 0.00904

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2021

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.8
Dann	Benign	0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148733454; hg19: chr16-58035194;